A human protein inherited from bacteria reveals an overlooked aspect of human immunity

What if the study of bacteria could illuminate our understanding of human immunity? In recent years, scientists have been exploring unexpected links between human proteins involved in the body’s defense mechanisms and certain bacterial immune proteins. Focusing on conserved immune domains originating from bacteria, termed “ancestral immune”, a team of researchers from Institut Curie, Institut Pasteur, and Inserm identified a novel human immune protein, SIRal. Published in Science on July 24, 2025, the study highlights the benefits of unraveling immune evolution, from bacteria to humans, to open promising avenues of research in immunotherapy.

It is widely assumed that scientists thoroughly mapped out the pathways of human innate immunity— the body’s first line of defense, which detects pathogens and triggers a rapid, protective response. However, the emerging field of ancestral immunity is challenging this long-held assumption. By exploring evolutionary links between bacterial and human proteins, researchers are finding that a significant number of proteins involved in human innate immunity are evolutionarily derived from bacterial immune defences. These proteins are not only structurally conserved: their immune functions have also been preserved—sometimes across billions of years of evolution.

SIRal, a prototypical ancestral immune module

In bacteria, the SIR2 (silent information regulator 2) protein domain plays a key role in defense against phages—viruses that specifically infect bacteria. When a phage invades a bacterium, SIR2 degrades a molecule essential for cell metabolism, leading to the death of the infected cell and the protection the rest of the bacterial population.

By reconstructing the evolutionary history of genes through phylogenetic analysis [1], a team led by Dr. Enzo Poirier, Inserm researcher and team leader at Institut Curie’s Immunity and Cancer Unit (Institut Curie, Inserm), and Dr. Aude Bernheim, head of the Molecular Diversity of Microbes Unit at Institut Pasteur, identified a human homologue of the SIR2 domain—SIRal. Results indicate that SIRal is a pivotal actor of innate immunity, through its ability to degrade NAD⁺, an essential metabolite involved in energy production.

Far from being a particularism of humans, SIRal proteins represent an ancient, well-shared family detectable in 19% of the eukaryotic genomes analyzed, spanning five major lineages. These findings confirm that bacterial-derived immune mechanisms are widely conserved across the tree of life, with potential implications for all eukaryotes.

In addition to the phylogenetic approach, Dr. Delphine Bonhomme (Poirier team), Hugo Vaysset (Bernheim team) and their colleagues demonstrated that SIRal acts as a central regulator of the TLR (Toll-like receptor) pathway —a family of receptors that detect pathogen-associated signals. This TLR pathway, regulated by SIRal, triggers the innate immune response, embodied by the expression of pro-inflammatory genes. The team showed that, without SIRal, the inflammatory response is severely impaired upon bacterial and viral infections.

“With SIRal, we show that protein modules inherited from bacterial immunity can play a central role in eukaryotic immune mechanisms, including in humans. The exloration of ancestral immunity thus gives us access to a previously unsuspected reservoir of immune mechanisms,” explains Enzo Poirier, Inserm researcher and team leader at Institut Curie.

“This discovery illustrates how evolution reuses ancient building blocks to create new functions: mechanisms that originated in bacteria billions of years ago still shape our immunity today,” adds Aude Bernheim, head of the Molecular Diversity of Microbes unit at Institut Pasteur.

A promising therapeutic target

Beyond its evolutionary implications, the discovery of SIRal could have clinical applications. Several autoimmune diseases are partly driven by the activation of TLR receptors. SIRal thus represents a novel therapeutic target, and its study could pave the way to innovative immunotherapies.